1. Field of the Invention
The present invention relates to novel globular amphiphilic polymers. More specifically, the present invention relates to low polydispersity particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain. The present invention also relates to methods for producing the particles. The invention particles can be used in a variety of applications, including removal of hydrophobic contaminants from aqueous solutions, recording materials, hydraulic fluids, coatings, chromatography, electrophoresis, drug delivery, catalysis, salvation, fat substitutes, delivery of herbicides and pesticides, combinatorial chemistry, DNA delivery, phase transfer reactions, and as fillers and reinforcement agents for plastics.
2. Description of Related Art
There is an interest in new classes of polymeric materials that have new and advanced physical, chemical, and mechanical properties. For example, Y. H. Kim reported hyperbranched polymers in Advanced Materials, 4, 764 (1992). Macrocycles were described by Y. Gan, et al. in Polymer Preparation, 34(1), 69 (1993). Rotaxanes were reported by Y. X. Shen, et al. in Macrocycles, 25, 2058 (1992). Two dimensional polymeric sheets have also been described (Stupp, S. I., et al., Science, 259, 59 (1993)).
Other polymeric materials with new and unusual behavior include dendrimers, described by D. A. Tomalia, et al. in Angewandte Chemie International Edition English, 29, 138 (1990). A review article on dendrimers is Ardoin, N., et al., Bulletin de la Socixc3xa9txc3xa9 Chimie, 132(9), 875 (1995). Another review of dendrimer research is found in Advances in Dendritic Materials, Ed. G. R. Newkome, JAI Press, Greenwich, Conn., 1994-95, Vol. 1-2.
Products created from these polymers possess unusual behavior when compared to traditional linear polymers. For example, rigid sphere and micellar dendrimers can encapsulate molecules and act as carriers or pharmaceutical delivery agents (Jansen, J. F. G. A., et al., Advanced Materials, 7(6), 561 (1995). Another example of how dendrimers can be used as carriers or pharmaceutical delivery agents is described by Hawker, C. J., et al., Journal of the Chemical Society, Perkins Transactions, 1, 1287 (1983)).
However, dendrimers are costly, time-consuming to synthesize, limited in their chemistry, and limited in their size range.
Block copolymers consisting of segments that possess different properties (for example, solubility, polarity, and rigidity) are well known to self-assemble into polymer micelles when placed in an appropriate solvent. Examples are found in Quin, A., et al., Macromolecules, 27, 120-26 (1994); Astafieva, I I, et al., Macromolecules, 26, 7339-7352 (1993); and Kataoka, K. et al., Journal of Controlled Release, 24, 119-132 (1993). However, these assembled structures are most often held together by hydrophobic interactions, which are not as strong as covalent bonds, and can be easily destroyed upon dilution of the solution containing polymer micelles, or by shear forces. Once the hydrophobic interactions are destroyed, the structures disassemble. Also, such structures typically have very short life times, for example less than a second.
Core-shell type polymer nonoparticles having a cross-linked core have been prepared from diblock copolymer films (Ishizu, K., et al., Polymer-Plastics Technology and Engineering, 31(7and8), 607 (1992); Saito, R., et al., Polymer, 35, 866 (1994)). Another example of core-crosslinked polymer nonoparticles is the stars described by Martin, M. K., et al., xe2x80x9cAnionic Polymerization,xe2x80x9d Ed. J. E. McGrath, ACS Symposium Series 166, American Chemical Society, 1981, pp. 557-590. Stars are limited in having only one polymerizable group per surfactant molecule. Other polymer nonoparticles with cross-linked cores have been prepared from cross-linkable diblock copolymers (Guo, A., et al., Macromolecules, 29, 2487 (1996)). The solid, cross-linked cores limit the absorptive properties, rigidity, and structures of these nanoparticles.
Until now, attempts to prepare core-shell type polymer nanoparticles having a crosslinked shell domain and an interior core domain have been unsuccessful. For example, D. Cochin, et al. reported in Macromolecules, 26, 5755 (1993) that attempts to prepare shell-crosslinked micelles failed when using amphiphilic molecules such as N-n-alkyl-N,N-dimethyl-N-(vinylbenzyl)ammonium chlorides.
S. Hamid and D. Sherrington reported in a kinetic analysis of micellar shell crosslinking, xe2x80x9cOn the contrary these kinetic parameters suggest that rapid exchange of polymerizable amphiphiles during the kinetic lifetime of a propagating radical should allow the possibility of growth to a high polymer (in reacting micelles at the expense of non-reacting ones), and the formation of particles of much bigger dimensions than micelles (i.e., a situation analogous to normal emulsion polymerization).xe2x80x9d They suggest that xe2x80x9cmonomer exchange is too rapid to form a xe2x80x98polymerized micellexe2x80x99.xe2x80x9d (Hamid, S. and Sherrington, D., xe2x80x9cPolymerized Micelles: Fact of Fancy?xe2x80x9d Journal of the Chemical Society, Chemical Communications, p. 936 (1986).)
L. Zhang, et al. reported in Science, 272, 1777 (1996) that morphological changes of micelles prepared in aqueous media from highly asymmetric polystyrene-b-poly(acrylic acid) can be obtained by the addition of calcium chloride, sodium chloride, or hydrochloric acid. Such morphological changes included clumping or clustering or bridging between micelles. The morphologically changed micelles are limited in their use because of their propensity to clump and because the stability of this system is highly dependent on pH and ionic strength.
Presently, there has not been a successful synthesis from amphiphilic agents or surfactants of a low polydispersity nanoparticle having a permeable, covalently crosslinked shell domain and an interior core domain. The references discussed above demonstrate continuing efforts to provide such a means of carrying or delivering chemical agents such as pharmaceuticals.
The present invention furthers the efforts described above by providing novel low polydispersity particles, pharmaceutical, agricultural, and other compositions, and methods of use therefor.
Accordingly, among its various aspects, the present invention provides low polydispersity globular macromolecules, particles, or nanoparticles as shown in FIG. 1, wherein the particles comprise amphiphilic copolymers, having a crosslinked shell domain or peripheral layer, which can be permeable, and an interior core domain.
The particles of the present invention can comprise a hydrophilic, crosslinked, permeable shell domain and a hydrophobic interior core domain. The amphiphilic copolymers of the particles of the present invention can be crosslinked via functional groups within the hydrophilic shell domain. Such crosslinking can be achieved by condensation reactions, addition reactions, or chain polymerization reactions.
In another embodiment of the present invention, the particles comprising amphiphilic copolymers, having a crosslinked shell domain and an interior core domain, comprise a hydrophobic, crosslinked shell domain, which can be permeable, and a hydrophilic interior core domain. The amphiphilic copolymers of these particles can be crosslinked via functional groups within the hydrophobic shell domain by condensation reactions, addition reactions, or chain polymerization reactions.
In yet another embodiment, the present invention provides a composition comprising amphiphilic copolymers, haveing a crosslinked shell domain, which can be permeable, and an interior core domain.
In another aspect, the present invention provides a pharmaceutical composition, comprising particles comprising amphiphilic copolymers having a crosslinked shell domain, which can be permeable, and an interior core domain, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition can further comprise a pharmaceutically active agent. The pharmaceutically active agent can be present within the particles.
In a further aspect, the present invention provides an agricultural composition, comprising particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, or an agronomically acceptable salt thereof, and an agronomically acceptable carrier, excipient, or diluent. The agricultural composition can further comprise a pesticidally/herbicidally active agent. The pesticidally/herbicidally active agent can be contained within the particles.
In yet a further aspect, the present invention also provides compositions suitable for use in foods, comprising particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, or a salt thereof acceptable for use in foods, and a carrier, excipient, or diluent suitable for use in foods.
In still a further aspect, the present invention also provides a fat substitute composition, comprising particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, or a gastronomically acceptable salt thereof, and a gastronomically acceptable carrier, excipient, or diluent. Such fat substitute compositions can be used in methods for simulating the presence of fat in food compositions or additives by including such fat substitute compositions in food materials.
The present invention also provides compositions suitable for use in cosmetics, comprising particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, or a cosmetically salt thereof, and a carrier, excipient, or diluent suitable for use in cosmetics.
In a further aspect, the present invention provides compositions suitable for use in chromatography or electrophoresis, comprising particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, or a chromatographically or electrophoretically acceptable salt thereof, and a chromatographically or electrophoretically acceptable carrier, continuous phase, mobile phase, or diluent. Such chromatographic or electrophoretic compositions can be used in methods for separating components of mixtures. These methods can comprise introducing a mixture of components to be separated into a column containing particles of the present invention or onto a substrate coated with particles of the present invention, passing an appropriate solvent through the column or over the particle-coated substrate to separate components of the mixture, and recovering or detecting separated components of the mixture. In the case of electrophoretic separations, an electric potential is applied to the column or particle-coated substrate using conditions which are known in the art. In another aspect, the present invention provides a method for delivering a nucleic acid molecule to a cell, tissue, or organ, comprising contacting the cell, tissue, or organ, in vivo or in vitro, with a composition containing a particle of the present invention and the nucleic acid molecule for a period time sufficient to deliver the nucleic acid molecule to the cell, tissue, or organ. The nucleic acid molecule can, for example, be present on the surface of the particle, or within the particle. The nucleic acid molecule can be DNA or RNA, for example, an antisense oligonucleotide, a vector, or any other type of nucleic acid molecule commonly employed in genetic engineering techniques. In still another aspect, the present invention provides a method for separating components of a solvent mixture, comprising contacting the solvent mixture with particles of the present invention for a period of time sufficient for one or more of the components of the solvent mixture to associate with the particles, and separating the particles from the remaining solvent.
In a further aspect, the present invention provides a method of synthesizing a polymer, including biopolymers, for example a nucleic acid, peptide, polypeptide, or protein, comprising associating or affixing a first monomer to an active site present on the surface of a particle of the present invention, and subsequently covalently binding successive monomers to the first monomer to produce a polymer chain. The polymer can remain attached to the particle or can be cleaved from the particle by methods known in the art. In still a further aspect, the present invention provides a method of synthesizing a derivative compound, comprising associating or affixing a substrate molecule to an active site present on the surface of a particle of the present invention, and subsequently performing reactions on the substrate molecule to produce the derivative compound. The derivative compound can remain attached to the particle or it can be cleaved from the particle by methods known in the art. Such a method can be used to prepare a single derivative compound or a mixture of derivative compounds.
In yet a further aspect, the present invention also provides a method of delivering a pharmaceutically active agent to a cell, tissue, or organ, comprising contacting the cell, tissue, or organ, in vivo or in vitro, with a composition containing an effective amount of particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, and further comprising a pharmaceutically active agent. The pharmaceutically active agent can be contained within the particles. In these methods, the contact is for a period of time sufficient to introduce the pharmaceutically active agent to the locus of the cell, tissue, or organ.
In yet a further aspect, the present invention also provides a method of delivering a pesticidally active agent to a plant or animal, comprising contacting the plant or animal with a composition containing an effective amount of particles comprising amphiphilic polymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, and further comprising a pesticidally active agent. The pesticidally active agent can be contained within the particles. In these methods, the contact is for a period of time sufficient to introduce the pesticidally active agent to the plant or animal.
In yet another aspect, the present invention also provides a method of reducing bile acid uptake in a mammal, comprising administering to the mammal a bile acid uptake-reducing effective amount of particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain, the particles being administered for a period of time effective to reduce bile acid uptake in the mammal.
In still another aspect, the present invention also provides a method of reducing blood serum cholesterol in a mammal, comprising administering to the mammal a blood serum cholesterol-reducing effective amount of particles comprising amphiphilic copolymers, having a crosslinked An shell domain, which can be permeable, and an interior core domain, the particles being administered for a period of time effective to reduce bile acid uptake in the mammal.
Other uses for the particles of this invention include size standards, use in coatings (for example, latex paints), and solvent compatiblizers.
In yet another aspect, the present invention also provides processes for the preparation of particles of the present invention.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent from this detailed description to those skilled in the art.